There is a critical need to improve the accuracy of preclinical drug efficacy and toxicity screening and testing through the development of human hepatocyte (liver) in vitro culture systems that more effectively mimic the human in vivo environment. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. Under Phase I SBIR R43DK091104, we developed a predictive rat primary hepatocyte system that restores morphology, function, transport, metabolism and respond to drugs and growth factors at nearer to in vivo levels. The principles to develop the rat system, translated to human primary hepatocytes, restoring morphology, function, metabolism and drug response at in vivo drug levels achieved in humans. To our knowledge, there are no commercially available systems that can achieve this level of hepatobiology and in vivo responsiveness in human primary hepatocytes ex vivo. The purpose of Phase II SBIR R44DK091104 is to further develop and validate a predictive primary human hepatocyte system for use in investigative toxicology, safety assessment and drug discovery with our commercial partners. Our Aims will achieve this using an integrated experimental, genomic and computational approach, screening more than 40 compounds in the system.